This Program Project Grant is a multidisciplinary effort involving the collaboration of clinicians, molecular biologists, geneticists and biostatisticians in a long term study of the molecular biology of the multiple endocrine neoplasia (MEN) type 2 and related syndromes. The study has six specific aims: 1) to identify and characterize the genes encoding for the MEN-2A and MEN-2B syndromes and for the non-MEN familial medullary thyroid carcinoma (FMTC) syndrome, 2) to determine if the clinical heterogeneity observed between families with the same disorder, or between related disorders (MEN-2A, MEN-2B and FMTC) is due to heterogeneity of the mutation in the predisposition gene, 3) to identify and characterize a novel suppressor gene on the short arm of chromosome 1,4) to characterize the biology of differentiation in medullary thyroid carcinoma (MTC), 5) to characterize the biology of differentiation in pheochromocytomas and, 6) to apply this information to the clinical management of patients with these diseases. These disease syndromes encompass a significant spectrum of endocrine neoplasia and in the context of defining the molecular mechanisms of endocrine oncogenesis the Program Project effort has a broad application to public health. The Program Project grant will consist of three Research Projects and four Core Components. Research Project 1 seeks to identify and characterize the gene(s) encoding for MEN-2A, MEN-2B and FMTC. A combination of linkage, mapping and gene cloning techniques will be employed to further localize and characterize the responsible gene(s) which is located in the pericentromeric region of chromosome 10. Research Project 2 seeks to map and identify a novel suppressor gene on the short arm of chromosome 1. In addition, patterns of genetic change, as defined by cytogenetic and molecular analysis will be correlated with tumor histology, the genetic background of the host and patient outcome. Research Project 3 investigates the biology of differentiation in pheochromocytomas. The molecular events involved in governing the differentiation of these cells derived from the neural crest will be studied primarily by characterizing the biologic activity of the nerve growth factor mediated early response gene, NGFI-A. The Core Components (Administration, Clinical Screening, Genetic Diagnosis and Counseling and Laboratory Resource) are essential and offer strong support to the investigators directing the Research Projects. The successful completion of these projects should provide important insights into the biological mechanism of malignant transformation and progression in these neuroendocrine tumors. In addition, a better understanding of the regulation of neural differentiation should be gained. Finally, we will have the biological regents in hand to identify predisposed individuals and lessen the morbidity and mortality associated with the MEN type 2 syndrome and related disorders.